Flatulence and defecation are perhaps what most of us associate with the stomach and intestines, which is not so surprising when you consider that the gastrointestinal tract is the body’s largest metabolic organ and gives everyone, sick or healthy, a daily reminder of its function. Less likely to occupy our minds is that the gut is the home to more than a thousand different species of bacteria, together weighing more than a kilo. A growing number of researchers, on the other hand, are now spending their days pondering the significance of this myriad of bacteria.
Medical Science met three researchers at the Karolinska Institute, Stockholm, Sweden, who are attempting in different ways to find out what our normal gut flora looks like, how it helps us to stay healthy, and what roles it plays in serious diseases. Elisabeth Norin, associate professor at the Department of Microbiology, Tumour and Cell Biology at Karolinska Institute, is studying faecal transplantation as a way of restoring gut health in people with diarrhoea caused by a bacterial imbalance.
There were anecdotal reports throughout the 20th century of the use of faeces from relatives to cure diarrhoea. One recent case in the US particularly caught the attention of the Swedish media: a woman who had suffered from diarrhoea for several months after repeated courses of antibiotics that knocked out her normal gut flora. Eventually the situation became so desperate that her husband donated his faeces for application into her rectum by means of an enema. Within hours the woman had completely recovered.
Elisabeth Norin and her colleagues have gone one step further. In the late 1990s a healthy middle-aged woman donated her faeces to Karolinska Institute. After careful analysis to check that it contained no pathogenic parasites, viruses or bacteria, the donated material was then treated in a way that allowed the normal gut flora to be cultured under controlled conditions.
“This gut flora culture is unique and occurs nowhere else in the world,” says Norin. “More than 100 patients have now been treated with it against diarrhoea, mainly in Sweden and Norway, and around 80 per cent have been cured – and we’ve seen no side-effects.”
One crucial resource for her research – and all other gut flora research – has been the unique germ- free rats and mice at Karolinska Institute. Since the 1950s, around 100 generations of rats have been raised in a completely sterile environment, originally delivered by Caesarean section, so that they have never kept any bacterial flora in their intestines or anywhere else in their bodies.
“By studying these germ-free animals, we saw that if we gave them faeces from animals raised in a normal environment, the normal gut flora became established very quickly,” says Norin. “But without a faecal transplant, the animals sometimes became ill with diarrhoea and could even die.”
But which of the bacteria in our faeces are the ones that matter?
“The truth is that we don’t know exactly what we’re transplanting, because of the difficulties in analysing the bacteria composition,” says Norin.
To find out what bacteria are to be found in the culture that has already cured 100 people of persistent diarrhoea, she has begun working with, among others, professor Lars Engstrand from the Department of Microbiology, Tumour and Cell Biology at Karolinska Institute. He is studying the culture using a technique developed at the Swedish Institute for Communicable Disease Control and Karolinska Institute a few years ago and now employed worldwide.
“We’ll also be analysing the bacterial flora in the faeces of patients with diarrhoea before and after treatment with the culture,” says Engstrand.
The technique is known as massively parallel pyro-sequencing and, put simply, analyses the complete DNA of the gut bacteria.
In one study, Lars Engstrand looked at the gut flora of identical twins where one was healthy and the other had the inflammatory bowel disorder Crohn’s disease.
“The twins’ gut flora differed in that the ones who were ill lacked certain groups of bacteria,” says Engstrand. “As far as our normal gut flora is concerned, it seems to be the case that the more species we have, the better.”
Massively parallel pyro-sequencing is opening doors which could lead to new medicines in the future. Elisabeth Norin hopes that one day it will be unnecessary to use her special culture to treat long-term diarrhoea. “Our dream is that once we know which bacteria we have in the culture, we can freeze-dry them and put them in a tablet or capsule,” she says.
Faecal transplantation also has potential in areas other than the treatment of diarrhoea. For example, research has been conducted in overweight patients. In a Dutch study, it emerged that insulin sensitivity in overweight patients with metabolic syndrome (a precursor to diabetes) increased when they were treated with faeces from slim donors. After six weeks, their blood lipids were also much improved. Patients who were treated with their own faeces, on the other hand, showed no change. This means that gut bacteria not only play a role in local conditions in the intestines, such as diarrhoea, but also seem to affect other diseases.
Professor Joseph Rafter from the Department of Biosciences and Nutrition at Karolinska Institute is trying to find out how. As vice-coordinator of the EU-funded project Tornado, he is involved in several different studies mapping the molecular mechanisms used by gut bacteria to impact the body’s physiology.
“We now know that bacteria in the intestines do not just have an effect on one another and the lining of the intestines,” says Rafter. “They can also ‘talk’ with tissues and organs a long way from the gut, such as the brain, liver and fat tissue. It seems quite clear that the gut flora also plays a role in diseases like diabetes, obesity and even autism in children.”
He has seen that gut bacteria release residues – metabolites – which can influence the host. These metabolites can be absorbed through the wall of the gut into the bloodstream, where they come into contact with target molecules in the body’s various organs. Rafter and his colleagues are now attempting to identify these target molecules locally in the lining of the gut and in the liver, intestines and fat tissue.
“What’s exciting is that the conversation – or cross – talk as it is known – between the bacteria and the host can be influenced from outside through diet. This means that if we can show how the bacteria’s metabolites affect a signalling pathway in the body which
is important for, say, fat deposition, we could influence this pathway from outside with a diet containing probiotic bacteria, for example.”
But it does not end there. Rafter is also interested in how diet, together with bacteria, can activate genes and cause them to produce proteins with particular effects. Studies of germ-free mice given a probiotic bacterium without any other change in diet revealed a decrease in fat deposition.
“We saw that many genes in the colon are activated by probiotics, and this in turn inhibited an enzyme that is important for the deposition of fat. Whether the results can be replicated in humans remains to be seen, but the genes we’ve looked at are the same as those found in the lining of the human gut.”
Another field that Rafter has spent several years studying is the possible preventive effects of probiotic bacteria when it comes to cancer of the colon.
“There are very clear indications that probiotics can protect against cancer in animal studies,” he says. “In humans, though, we cannot yet say any more than that there is a possible protective effect against colon cancer.”
Like Elisabeth Norin, Joseph Rafter dreams of new treatments in the future, and his hopes too hang on analysis of the bacteria’s DNA.
“It would be wonderful to be able to come back in a hundred years and see what this research has led to,” he says. “I think that eventually we’ll have a kind of library of gut bacteria genes. We’ll then be able to go into this library and pick out a single bacterium that we know releases a metabolite that regulates a particular disease, and use it to treat patients.”